ACE Inhibitors and Statins in Adolescents with Type-1 Diabetes

Julia Lvovich, Mercer University College of Pharmacy

Type 1 diabetes most frequently occurs in children and adolescents, although this autoimmune disease can occur at any age. In type 1 diabetes, beta cells are destroyed by the body’s own immune system, causing a complete insulin dependence. Due to the early onset of disease and difficulty of glycemic control, type 1 diabetic patients are at an increased risk of long-term complications, such as diabetic kidney disease. [1]

During early stages of diabetic kidney disease, kidneys begin removing trace amounts of albumin from the blood and may lead to microalbuminuria. It is suggested that an increase in albumin excretion during adolescence predicts the development of microalbuminuria and diabetic kidney disease. [1] Currently, there is no established clinical criteria for early interventions based on microalbuminuria; however, it is suggested that management may prove beneficial for type 1 diabetics. In adult diabetic (type 1 and 2) patients, microalbuminuria is managed by angiotensin-converting enzyme (ACE) inhibitors; however, in adolescents there is a lack of evidence to support the use of preventative measures to reduce the incidence of and progression to diabetic kidney disease. [2,3]

Inhibitors and statins in adolescents with type one diabetes
Design Double blind, randomized, placebo-controlled trial; N= 443
Objective To determine whether ACE inhibitors and statins are beneficial in adolescents with type one diabetes
Study Groups ACE inhibitor (quinapril 5-10mg) and placebo (n= 111)

Statin (atorvastatin 10mg) and placebo (n= 112)

ACE inhibitor (quinapril 5-10mg) and statin (atorvastatin 10mg) (n=111)

Placebo and placebo (n=109)

 

Methods Inclusion Criteria:

·      Age 10-16 years old

·      Diagnosed with type one diabetes at least one year earlier

·      Albumin to creatinine ratio values in the upper third of the range

 

Exclusion Criteria:

·      Non-type one diabetes

·      Pregnancy

·      Severe hyperlipidemia

·      Presence of renal disease that was not associated with type one diabetes

 

At baseline visit, laboratory and vital signs were obtained. After randomization into study groups, patients were seen after one month, and then every three months. At every six months, blood samples and urine samples were collected for an albumin-to-creatinine ratio assessment. Final assessments occurred after a minimum of two years and a maximum of four years.

 

Duration May 2009 to August 2013
Primary Outcome Measure Change in albumin to creatinine ratio.
Baseline Characteristics
ACE Inhibitor

n= 222

Placebo

n= 221

Statin

n= 223

Placebo

n= 220

Age- yr 12.4±1.4 12.4±1.4 12.4±1.4 12.4±1.4
Duration of type 1 diabetes
<5 years 47.3 48.0 47.5 47.7
5-10 years 52.7 52.0 52.6 52.3
Albumin- to –creatinine ratio median* 10.8 10.7 11.0 10.5
Microalbuminuria – % 0.50 0.90 0.90 0.50
Retinopathy -% 13.3 10.6 10.6 13.3
Cholesterol level, SD
Total 172.5±34.4 169.0±34.4 171.7±34.4 169.4±34.8
LDL (low-density liporprotein) 91.6±26.3 89.3±24.7 91.6±25.1 89.3±25.5
HDL (high density lipoprotein) 60.7±14.7 58.8±14.3 59.6±14.3 59.9±14.7
Non-HDL 111.4±34.2 110.2±33.3 112.2±33.6 109.4±34.4
TG (triglyceride) level 86.8±51.4 95.7±61.1 91.2±54.0 92.1±60.2

SD- Standard deviation

*Urinary albumin-to-creatinine ratio is based on measurement of albumin in milligrams and creatinine in grams. To convert the values for the albumin to creatinine ratio to values with creatinine measured in millimoles, multiply by 0.113.

Results  

ACE inhibitors vs Placebo Statins vs Placebo

 

Effect

 

95% CI

 

P value

 

Effect

 

95% CI

 

P value

 

Creatinine (mg/dl)

 

-0.006

 

-0.02, 0.01

 

0.48

 

-0.007

 

-0.02, 0.01

 

0.39

 

Log ACR

 

-0.01

 

-0.05, 0.03

 

0.65

 

0.01

 

-0.02, 0.05

 

0.45

 

Total cholesterol (mg/dl)

 

2.46

 

-3.46, 8.39

 

0.42

 

-23.7

 

-29.5, -17.8

 

<0.001

 

LDL-cholesterol (mg/dl)

 

0.11

 

-4.51, 4.74

 

0.96

 

-21.3

 

-25.9, -16.7

 

<0.001

 

HDL-cholesterol (mg/dl)

 

0.15

 

-1.97, 2.27

 

0.89

 

-0.08

 

-2.17, 2.01

 

0.94

 

non-HDL-cholesterol (mg/dl)
Triglycerides (mg/dl)
2.72

 

-3.36, 8.80

 

0.38

 

-23.48

 

-29.47, -17.49

 

<0.001

 

Hazard ratio

 

95% CI

 

P value

 

Hazard ratio

 

95% CI

 

P value

 

Incidence of microalbuminuria

 

0.57

 

0.35, 0.94

 

0.03

 

0.98

 

0.61, 1.58

 

0.93

 

Retinopathy 2-step progression

 

1.12

 

0.78, 1.60

 

0.53

 

0.93

 

0.65, 1.32

 

0.67

 

Retinopathy 3-step progression

 

1.03

 

0.71, 1.50

 

0.87

 

0.83

 

0.58, 1.20

 

0.33

 

ACR= albumin/creatinine ratio, HDL: high density lipoprotein; hs-CRP: high sensitivity C-reactive protein; LDL: low density lipoprotein

 

Area under the curve for albumin- to creatinine ratio:

·      ACE inhibitors (effect, – 0.01; 95% CI, -0.05 to 0.03)

·      Statin (effect, 0.01; 95% CI, -0.02 to 0.05).

 

Secondary outcomes (α= 0.01)

ACE inhibitors:

Incidence of microalbuminuria: (p= 0.046; log-rank); adjusted hazard ratio 0.57 (95% CI, 0.35 to 0.94; p= 0.03)

 

ACE inhibitors did not affect retinopathy progression, and there was non-significant lower progression of retinopathy with statins.

 

Statins:

Incidence of microalbuminuria: Adjusted hazard ratio, 0.98; 95% CI, 0.61-to 1.58; p= 0.93

·      Statin treatment was associated with lower levels of total, LDL, non-HDL cholesterol, and triglycerides.

 

Adverse Events Common Adverse Events:

Vomiting, %

·      ACE inhibitor plus placebo (n= 5)

·      ACE inhibitor plus statin (n=4)

·      Placebo plus placebo (n=4)

·      Statin plus placebo (n=8)

 

Gastrointestinal disorder, %

·      ACE inhibitor plus placebo (n= 9)

·      ACE inhibitor plus statin (n=10)

·      Placebo plus placebo (n=11)

·      Statin plus placebo (n=11)

 

Table 2:Serious Adverse Events

ACE Inhibitor plus placebo (n= 111) ACE inhibitor plus statin (n= 111) Placebo plus placebo (n= 109) Statin plus placebo (n= 112)
Gastrointestinal disorder 9 (8.1) 10 (9.0) 11 (10.1) 11 (9.8)
Diabetic ketoacidosis 17 (15.3) 9 (8.1) 8 (7.3) 18 (16.1)
Hyperglycemia 4 (3.6) 3 (2.7) 1 (0.9) 7 (6.2)
Psychiatric disorder 2 (1.8) 6 (5.4) 6 (5.5) 2 (1.8)
Renal or Urinary disorder 0 1 (0.9) 1 (0.9) 0
Infection or infestation 11 (9.9) 13 (11.7) 14 (12.8) 8 (7.1)
Injury Poisoning, or procedural complication 14 (12.6) 11 (9.9) 10 (9.2) 14 (12.5)

 

 

Serious Adverse Events: During ACE therapy, 56 patients required a dose reduction from 10mg to 5mg due to postural hypotension.

·      Hypotensive episode (n= 1)

·      Clinically significant decrease in glomerular filtration rate (GFR) (n= 2)

·      Elevated levels of alanine aminotransferase (n= 1)

Percentage that Discontinued due to Adverse Events: Not disclosed
Study Author Conclusions ACE inhibitor and statins did not affect albumin-to-creatinine ratio

 

The results suggest that there are no additional benefits of ACE inhibitor or statins in type 1 diabetic adolescents. The study had robust design and met power, which minimizes the likelihood of type II error. Additionally, separating the sample into four different groups allowed the investigators to analyze the independent effects of ACE inhibitor or statins, instead of only assessing the combination effects. The study also monitored adherence with electronic track caps, which showed >70% adherence. This may further strengthen the outcomes as lower adherence rates may falsely underestimate the drug effects. Finally, albumin to creatinine ratio inclusion criteria was also appropriate because such patients may be at a higher risk of disease progression and may be the population of interest in clinical settings.

The study is not without limitations. Although monitoring adherence using electronic caps is common in clinical studies, it may not be a true reflection of pill taking behavior; therefore, if the true adherence was <70%, the effects may be falsely underestimated. Regarding choice of medications, quinapril use in pediatrics is an off-label use, and the safety and efficacy in children has not been studied. [4] However, according to the National Heart, Lung, and Blood Institute (NHLBI), quinapril may be used at 5-10 mg initially then titrated up to 80 mg daily for hypertension. [5] Therefore, the doses used in this study appear to be relatively low (5-10 mg), although some patients experienced side-effects and the indications are different. The dose of atorvastatin was appropriate for this population. [6]

Lastly, evidence suggests that delayed effects may occur with the study drugs, which may not have been observed during the study duration. Overall, based on the study, until further evidence is available, routine use of ACE inhibitors and statins for primary prophylaxis is not recommended in in adolescents with type 1 diabetes.

References

[1]. Dunger DB, Schwarze CP, Cooper JD, et al. Can we identify adolescents at high risk for nephropathy before the development of microalbuminuria? Diabet Med 2007;24:131-6.

[2]. Marcovecchio ML, Chiesa ST, Bond S, et al. ACE Inhibitors and Statins in Adolescents with Type 1 Diabetes. N Engl J Med. 2017;377(18):1733-1745.

[3] American Diabetes Association. Standards of Medical Care in Diabetes 2017. Diabetes Care 2017; 40(Suppl. 1):S6–S10. January 2017.

 

[4] AccuprilÒ [package insert]. New York, NY. Parke-Davis Division of Pfizer Inc., December 2011.

 

[5] Expert Panel Report 3:Guidelines for management of Asthma. Bethesda MD: National Heart,Lung, and Blood Institute; 2007- [2017 December 11]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK7232/?report=reader

[6] LipitorÒ [package insert]. New York, NY. Parke-Davis Division of Pfizer Inc., June 2009.

 

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